Attempts have been made to cure diseases such as a cancer by inhibiting angiogenesis. Angiogenesis is a physiological phenomenon in which a new blood vessel branches from existing blood vessel, and plays an important role in, for example, organogenesis and the development of a corpus luteum in the early development of an animal, and wound healing. It is known that excess occurrence of this angiogenesis participates in many diseases such as a malignant tumor, psoriasis, rheumatism, atherosclerosis, and retinopathy (see non-patent literatures 1 and 2).
The process of angiogenesis includes growth, differentiation, migration, tube formation of a vascular endothelial cell, and the like. Angiogenesis is mainly controlled by several different growth factors, and their receptors. Of these growth factors, a vascular endothelial growth factor (VEGF) is presumably the most important control factor in blood vessel formation. VEGF is a dimer glycoprotein specific to endothelial cells. Overexpression of VEGF occurs in various tumors, and causes blood vessel formation of a tumor. Overexpression of VEGF occurs in other pathological conditions such as chronic rheumatoid arthritis and retinal neovascularization.
The bond of two tyrosine kinase receptors, i.e., VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) intervenes the angiogenesis promoting action of VEGF. Since the tyrosine kinase activity of VEGFR2 is higher than that of VEGFR1, VEGFR2 is probably a central signal transmission path of angiogenesis.
When VEGF bonds to VEGFR2, dimerization and autophosphorylation of the receptor occur. This causes phosphorylation and activation of several downstream signaling proteins including Akt, ERK1/2, and p38MAPK. These signaling proteins play important roles in the survival, growth, migration, and reorganization of cancer cells.